Administrative supplement to Regulation of mitochondrial DNA homeostasis and neuroinflammation by Fascin

Fascin 调节线粒体 DNA 稳态和神经炎症的行政补充

基本信息

批准号：
10808414
负责人：
Yongchao Charles Ma
金额：
$ 8.47万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10808414
关键词：
Actins Administrative Supplement Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Biogenesis Brain Bundling Cells Complex DNA Data Defect Development Disease Dominant-Negative Mutation Extravasation F-Actin Filopodia Goals Hippocampus Homeostasis Impairment Inflammasome Inflammatory Knockout Mice Mediating Membrane Microfilaments Mitochondria Mitochondrial DNA Mus Nerve Degeneration Neurodegenerative Disorders Oxidative Phosphorylation Oxidative Stress Pathogenesis Pathogenicity Pathologic Persons Phenotype Physiological Play Process Proteins Regulation Research Role Symptoms Testing Tumor Cell Invasion Virus brain tissue cell motility crosslink cytokine effective therapy fascin human old age (65+)in vivo insight mitochondrial dysfunction mouse model neuroinflammation neuron loss novel novel therapeutic intervention respiratory therapeutic development transgene expression

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD), the most common neurodegenerative disorder, affects one in ten people age 65 and older. Due to limited understanding of mechanisms underlying AD pathogenesis, there is no effective treatment for this devastating disease. The goal of this application is to investigate an unexpected role for actin bundling protein Fascin in regulating mitochondrial nucleoid DNA (mtDNA) homeostasis, oxidative phosphorylation (OXPHOS), mitochondrial oxidative stress, neuroinflammation, and neurodegeneration, as well as how dysregulation of these processes contributes to AD pathogenesis. Fascin is an actin bundling protein essential for the cross-linking of actin filaments into compact and rigid bundles. The current paradigm posits that Fascin promotes cell migration and tumor invasion by generating protrusive membrane structures such as filopodia. We recently made the surprising finding that depletion of Fascin disrupts mitochondrial F- actin bundling, which in turn causes abnormal mitochondrial respiratory complex biogenesis and impaired mitochondrial OXPHOS, suggesting a novel role of Fascin in the regulation of mitochondrial function. Mechanistically the mitochondrial dysfunction in Fascin depleted cells was due to increased mtDNA aggregation and leakage. Given that mtDNA can robustly induce inflammasome activation and inflammatory cytokine expression, Fascin deficiency may play an unexpected role in causing neuroinflammation. Importantly, we found that Fascin is cleaved into a 37kDa functionally dominant-negative form in the brains of AD patients and AD mouse models. Virus-mediated expression of Fascin in AD mouse hippocampus mitigated disease symptoms. In addition, Fascin knockout mice we generated showed profound mitochondrial defects and significant loss of neurons in the brain. Based on these preliminary data, we hypothesize that Fascin controls mitochondrial function and mtDNA homeostasis in the brain. Fascin functional deficiency in AD leads to significant mitochondrial defects, neuroinflammation and neurodegeneration. To test the hypothesis, in Aim 1 we will define the role of Fascin in regulating mitochondrial function, mtDNA homeostasis, neuroinflammation and neuronal cell death in the mouse brain in vivo. In Aim 2 we will investigate the functional deficiency of Fascin caused by proteolytic cleavage during the course of AD pathogenesis using brain tissues from AD patients and mouse models, and to elucidate mechanisms underlying how Fascin functional deficiency causes mtDNA leakage, oxidative stress, neuroinflammation, and degeneration. In Aim 3 we will study the effects of transgenic expression of Fascin on alleviating AD pathological phenotypes and disease symptoms in mice. Successful completion of the proposed studies will reveal Fascin’s novel role in regulating mitochondrial function, mtDNA homeostasis, neuroinflammation and neurodegeneration. Investigating Fascin functional deficiency in AD will help understand disease pathogenic mechanisms and facilitate therapeutic development.

项目摘要/摘要阿尔茨海默氏病（AD）是最常见的神经退行性疾病，影响十分之十的人年龄 65岁及以上。由于对AD发病机理的机制的了解有限，因此没有有效治疗这种毁灭性疾病。该应用的目的是调查意外角色肌动蛋白束蛋白fascin在调节性线粒体核苷DNA（mtDNA）稳态中，氧化磷酸化（OXPHOS），线粒体氧化应激，神经炎症和神经退行性，AS 以及这些过程的失调如何导致AD发病机理。法斯汀是肌动蛋白捆绑蛋白质对于肌动蛋白丝与紧凑和刚性束的交联所必需的蛋白质。当前的范式假定Fascin通过产生突出的膜结构来促进细胞迁移和肿瘤侵袭例如丝状。最近，我们提出了一个令人惊讶的发现，即Fascin的耗竭会破坏线粒体F- 肌动蛋白束，进而导致线粒体呼吸复合物生物发生异常并受损线粒体oxphos，表明FASTIN在线粒体功能调节中的新作用。从机械上讲，fascin depthd细胞中的线粒体功能障碍是由于mtDNA增加聚集和泄漏。鉴于mtDNA可以牢固诱导炎症体激活和炎症细胞因子表达，fascin缺乏症可能在引起神经炎症中起意外的作用。重要的是，我们发现fastin被裂解成大脑中功能优势的37KDA AD患者和AD小鼠模型的模型。 AD小鼠海马中FASTIN的病毒介导的表达减轻疾病症状。此外，我们产生的Fascin淘汰小鼠表现深刻线粒体缺陷和大脑中神经元的明显丧失。基于这些初步数据，我们假设Fascin控制大脑中的线粒体功能和mtDNA稳态。 Fascin AD的功能缺乏会导致明显的线粒体缺陷，神经炎症和神经变性。为了检验假设，在目标1中，我们将定义fastin在调节中的作用线粒体功能，mtDNA稳态，小鼠脑中神经炎症和神经元细胞死亡体内。在AIM 2中，我们将研究由蛋白水解裂解引起的fascin的功能缺乏。使用AD患者和小鼠模型的脑组织AD发病机理的过程，并阐明 fascin功能缺乏的基础机制导致mtDNA泄漏，氧化应激，神经炎症和变性。在AIM 3中，我们将研究Fascin的转基因表达的影响减轻小鼠的AD病理表型和疾病症状。成功完成拟议的研究将揭示法斯汀在确定线粒体功能MTDNA稳态中的新作用，神经炎症和神经变性。调查AD的Fascin功能缺陷将有助于了解疾病的致病机制并促进治疗性发育。